Abstract
Cholestasis comprises aetiologically heterogeneous conditions characterized by accumulation of bile acids in the liver that actively contribute to liver damage. Sirtuin 1 (SIRT1) regulates liver regeneration and bile acid metabolism by modulating farnesoid X receptor (FXR); we here investigate its role in cholestatic liver disease. We determined SIRT1 expression in livers from patients with cholestatic disease, in two experimental models of cholestasis, as well as in human and murine liver cells in response to bile acid loading. SIRT1‐overexpressing (SIRToe) and hepatocyte‐specific SIRT1‐KO (knockout) mice (SIRThep–/–) were subjected to bile duct ligation (BDL) and were fed with a 0.1% DDC (3,5‐diethoxycarbonyl‐1,4‐dihydrocollidine) diet to determine the biological relevance of SIRT1 during cholestasis. The effect of NorUDCA (24‐norursodeoxycholic acid) was tested in BDL/SIRToe mice. We found that SIRT1 was highly expressed in livers from cholestatic patients, mice after BDL, and Mdr2 knockout mice (Mdr2–/–) animals. The detrimental effects of SIRT1 during cholestasis were validated in vivo and in vitro. SIRToe mice showed exacerbated parenchymal injury whereas SIRThep–/– mice evidenced a moderate improvement after BDL and 0.1% DDC feeding. Likewise, hepatocytes isolated from SIRToe mice showed increased apoptosis in response to bile acids, whereas a significant reduction was observed in SIRThep–/– hepatocytes. Importantly, the decrease, but not complete inhibition, of SIRT1 exerted by norUDCA treatment correlated with pronounced improvement in liver parenchyma in BDL/SIRToe mice. Interestingly, both SIRT1 overexpression and hepatocyte‐specific SIRT1 depletion correlated with inhibition of FXR, whereas modulation of SIRT1 by NorUDCA associated with restored FXR signaling. Conclusion: SIRT1 expression is increased during human and murine cholestasis. Fine‐tuning expression of SIRT1 is essential to protect the liver from cholestatic liver damage.
Highlights
The term ‘cholestatic liver disease’ includes a broad spectrum of aetiologically heterogeneous hepatobiliary disorders, mainly comprising primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) in adults. These conditions are characterised by accumulation of bile acids in the liver, leading to hepatocellular necrosis and apoptosis, progressive fibrosis and end-stage liver disease[1,2,3]
Current therapeutic approaches for treating cholestasis mainly rely on the use of Ursodeoxycholic acid (UDCA); this treatment has no proven efficacy for PSC and a proportion of patients with PBC[2, 3]
The therapeutic options for such unresponsive patients are currently limited though there have been recent promising advances including the use of 24-norursodeoxycholic acid (NorUDCA)(4), which has shown to improve liver function in PSC patients in a recent clinical trial[5]
Summary
The term ‘cholestatic liver disease’ includes a broad spectrum of aetiologically heterogeneous hepatobiliary disorders, mainly comprising primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) in adults. These conditions are characterised by accumulation of bile acids in the liver, leading to hepatocellular necrosis and apoptosis, progressive fibrosis and end-stage liver disease[1,2,3]. Current therapeutic approaches for treating cholestasis mainly rely on the use of Ursodeoxycholic acid (UDCA); this treatment has no proven efficacy for PSC and a proportion of patients with PBC[2, 3].
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